6beta,19-oxido androstane derivatives



United States Patent P 3,001,989 6;3,19-0XIDO ANDROSTANE DERIVATIVESHoward J. Ringold and Albert Bowers, Mexico City,

Mexico, assignors to Syntex S.A., Mexico City, Mexico, a corporation ofMexico No Drawing. Filed July 29, 1960, Ser. No. 46,076

Claims priority, application Mexico Jan. 6, 1960 13 Claims. (Cl.260--239.55)

following formula:

In the above formula R represents keto, fi-hydroxy or p-acyloxy and R'represents keto,

wherein R represents hydrogen or an aliphatic hydrocarbon group,saturated or unsaturated, containing up to 8 carbon atoms. When R and Rare keto, double bonds may be present at C-1,2 and C-4,5.

The acyl groups are derived from hydrocarbon carboxylic acids containingup to 12 carbon atoms, saturated or unsaturated, of straight, branched,cyclic or cyclicaliphatic chain, aromatic and may be substituted byfunctional groups such as hydroxyl, acyloxy of up to 12 carbon atoms,alkoxy of up to 8 carbon atoms, amino or halogen. Typical ester groupsinclude the acetate, propionate, butyrate, hemisuccinate enanthate,caproate, benzoate, phenoxyacetate, trimethylacetate, aminoacetate,cyclopentylpropionate and B-chloropropionate.

Typical aliphatic hydrocarbon groups at 0-170: are methyl, ethyl,propyl, butyl, vinyl, l-propenyl, 2 butenyl, ethinyl and l-butinyl.

The novel oxido compounds of the present invention also lower the bloodcholesterol levels, are cardiac antifibrillatory agents, have analgesicproperties and are bacteriostatic against gram positive bacteria.

' The novel compounds of the present invention are prepared by a processillustrated by the following equation:

a5 mp5 I II Patented Sept. 26, 1961 y no III VI VII In the aboveequation Ac represents the acetyl radical; however, other acyl groupsmay be substituted therefor.

In practicing the process outlined above, the starting material,3[3,17,8-diacetoxy-androstan-GB-ol, described by Shopee et :aL, J. Chem.Soc., 1953, 245, can be conveniently prepared by reacting the diacetateof A -androstenediol with hypobromous acid to form the 3,17- diacetateof 5u-bI'OmO-filldIOStQIlC-Iifififi,17fla111i01 which upon subsequentoxidation with 8 N chromic acid is transformed into5a-bromo-androstane-3/3,17B-diol-6-one. The latter compound isreductively debrominated to form the diacetate ofandrostane-Sfl,l7B-diol-6-one which is then hydrogenated to produce thedesired 3,17-diacetate of androstane-3p,6,8,l7/8-triol (I) The lattercompound (I) is treated with lead tetraacetate, preferably in a solventsuch. as benzene at reflux temperature. Other solvents which are inertto the reaction, for example, aromatic hydrocarbons such as toluene,xylene or ethers such as dioxane, tetrahy-drofurane,

the methyl ethers of propylene glycol or halogenated alphatichydrocarbons such as carbon tetrachloride may replace the benzene andthe reaction may then proceed below the boiling point of the solvent.The thus formed diacetate of 6p,l9-oxido-androstane-3,B,17fl-diol (II)is hydrolyzed as by refluxing with dilute methanolic potassium hydroxideto form the free diol, namely, 65,19- oxido-androstane-3fl,17p-dio1(III) which is oxidized by reaction with 8 N chromic acid to form the6,3,19-oxidoandrostane-3,17-dione (IV).

For introduction of a double bond at C-l,2 the latter compound (IV) istreated with two molar equivalents of bromine in acetic acid containinga trace of hydrogen bromide, at room temperature; the thus formed 2,16-dibromo-Gp,19-oxido-androstane-3,l7-dione (V) is selectivelydehydrobrominated at 02 by refluxing with calcium carbonate in mixturewith dimethylformamide for about half an hour to form the16-bromo-65,19-oxido- A -androstene-3,l7-dione (VI). For completedehydrobromination the latter compound is dissolved in acetone andtreated for a short time with an excess of chromous chloride at C. tothus form 65,19-oxido-A1-androstene- 3,17-dione (VII). By refluxing thelatter compound in dioxane with2,3-dichloro-5,6-dicyano-1,4-benzoquinone for a period of time in theorder of 20 hours, there is formed the 65,19-oxido Aandrostadiene-3,17-dione (VIII). Alternatively the latter compound maybe formed directly from 65,19-oxido-androstane-3,17-dione (IV) byrefluxing for 24 hours with the 2,3-dichloro-5,6-dicyano-lA-benzoquinone in dioxane solution.

The following equation illustrates a method for the introduction of a17a-aliphatic hydrocarbon-175-hydroxy grouping:

O O 0 ll H2C H2O IV IX 9H 0 n" a H20 7 H20 0 l 0 HO HO XI X 911 (|)R n nH2O HzC I 0 0 a a XII XIII In the above equation, R and R representhydrogen or a hydrocarbon carboxylic acyl group of the type mentionedhereinabove and R represents an aliphatic hydrocarbon radical saturatedor unsaturated, containing up to 8 carbon atoms.

The 17-keto group of 65,19-oxido-androstane-3,17- dione (IV) ispreferentially protected by formation of the G17 cycloalkyleneketal,achieved by refluxing the 65,19-oxido-androstane-3,17-dione with adihydric alcohol such as ethylene glycol in a solvent such as benzeneand in the presence of p-toluenesulfonic acid for about 6 hours followedby subsequent reduction of the thus formed 65,19 oxido 17ethylenedioxy-androstane-3-one (IX) with a double metal hydride such assodium borohydride to produce65,19-oxido-17-ethylenedioxy-androstane-35- 01 which is converted bytreatment with p-toluenesulfonic acid in acetone into'65,l9-oxido-androstan-35-ol- 17-one (X). The latter compound is thenreacted with an aliphatic hydrocarbon magnesium halide to convert.

the 17-keto 'group into the 175-hydroxy-1h-aliphatic hydrocarbongrouping. Thus, by reaction with methyl magnesium bromide, thel7u-methyl-175-hydroxy grouping is formed and by similar reaction withan ethyl, vinyl, ethinyl or butenyl Grignard reagent, there is formedthe 175-hydroxyl compound with the respective aliphatic hydrocarbonradical at C-l7a. Alternatively, the 17methyl group is introduced byreaction with ethyl-lithium and the ethinyl group can be introduced bythe conventional reaction with potassium acetylide. The thus formed65,19-oxido-17a-hydrocarbon-androstane-35,175- diol (XI) is esterifiedby conventional methods with a hydrocarbon carboxylic acid anhydride orchloride containing up to twelve carbon atoms of the type heretoforementioned to produce the corresponding 3-monoesters (XII).Esterification of the tertiary hydorxyl group at C-175 is effected byreaction with the acid anhydride in benzene solution and in the presenceof catalytic amounts of p-toluenesulfonic acid, with simultaneousesterification of a free hydroxyl group at 0-3 (XIII). By theseesterification methods there is prepared 3-mono esters as well as3,17-diesters having identical ester groups or ester groups diflerentfrom each other.

The diesters of 65,19-oxido-17a-aliphatichydrocarbonandrostane-35,175-diol (XIII) are also useful intermediatesfor the preparation of the novel 6,19-lact0nes.

having an aliphatic hydrocarbon radical at C-l'la, which lactones arehypotensive agents having bacteriostatic activity against gram positivebacteria as well as anabolic agents having low androgenicity and arealso useful in the treatment of premenstrual tension.

The conversion of the 65,19-oxido diesters into the lac- In the aboveequation, R R and R have the same meaning as previously set forth.

In practicing the above process, a diester of 65,19- oxido-17a-aliphatichydrocarbon androstane-3 5,175-di0l (XIII) is oxidized by reaction withchromium trioxide in acetic acid under reflux condition to form thecorresponding diester of the 6,19-lactone of Net-aliphatichydrocarbon-androstane-35,65,175-triol-19-carboxylic acid (XIV). Uponalkaline hydrolysis of the ester groups, there is formed the6,19-lactone of the Hot-aliphatic hydrocarbonandrostrane 35,65,175triol-19-carboxylic acid (XV) which upon oxidation with chromic acid inaqueous acetic acid is converted into the 6,19-lactone of 17a-aliphatichydrocarbon androstane-65,175'diol-3-one-19-carboxylic acid.

The following examples serve to illustrate but are not intended to limitthe scope of the present invention:

Example I A suspension of 10 g. of the diacetate of A -androstene-35,175-diol in cc. of dioxane was treated with 12 cc. of 0.46 Nperchloric acid and then with 4 g. of N-bromoacetamide;- theN-bromoacetamide was added little by little, with stirring, in thecourse of 1 hour, in the dark and maintaining the temperature around 15C. The mixture was stirred for 1 hour further in the dark at roomtemperature; it was then decolorized by the addition of aqueous sodiumbisulfite solution, 1 1t. of water was added and the product wasextracted with methylene chloride; the extract was washed with water,dried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure and at room temperature. The residue consisted of the3,17-diacetate of 5a-bromo-androstane-3;8,6B, 17fi-triol.

There was prepared 100 cc. of an 8 N solution of chromic acid from 26.7g. of chromium trioxide, 23 cc. of concentrated sulfuric acid anddistilled water. A solution of 10 g. of the 3,17-diacetate ofSa-brOmc-androstane- 35,65,17B-trio1 in 100 cc. of acetone was cooled to0 C. and treated with the 8 N solution of chromic acid until thecharacteristic color of chromium tn'oxide persisted in the mixture. The8 N solution of chromic acid was added in a slow stream, under anatmosphere of nitrogen, with stirring and at 0 C. The mixture was thenstirred at 0 C. under an atmosphere of nitrogen for 2 minutes further,poured into ice water and the precipitate was collected by filtration,washed with water and dried under vacuum, thus affording the diacetateof Sa-bromo-andmstane-3;8,l7[3-diol-6-one.

A mixture of the above compound, 10 g. of zinc dust and 250 cc. ofglacial acetic acid was heated at 90 for 2 hours, at the end of which itwas filtered through celite under an atmosphere of nitrogen and thefiltrate was con centrated to a small volume under reduced pressure;after cooling it was diluted with ice water and the precipitate of thediacetate of androstane-3 3,17/i-diol-6-one was collected by filtration,washed with water and dried.

The above crude diacetate of androstane-3B,17B-diol- 6-one was dissolvedin a mixture of 80 cc. of absolute ethanol and 120 cc. of glacial aceticacid and hydrogenated in a Parr instrument at 50 atmospheres, in thepresence of 1.2 g. of platinum oxide, with vigorous stirring and at roomtemperature for24 hours; the catalyst was then removed by filtration andthe filtrate was evaporated to dryness under reduced pressure; theresidue was purified by chromatography on neutral alumina. There wasthus obtained the 3,17-diacetate of androstane- 3B,6fi,17/8-triol, M.P.130-132 [ab-24.

Example I] To a solution of 4 g. of the 3,17-diacetate o-fandrostane-3B,6,B,17fl-triol in 150 cc. of anhydrous benzene was added 6g. of lead tetraacetate and the mixture was refluxed for 18 hours. Afterfiltering the filtrate was diluted with water, the benzene layer wasseparated, washed with water and the benzene was evaporated underreduced pressure; by chromatography of the residue on neutral alumina,there was obtained the diacetate of6fl-l9-oxidoandrostane-3;8,17,H-diol; M.P. 140-141 C. [or] +24.5(chloroform).

A solution of 2.0 g. of the above compound in 100 cc. of 2% methanolicpotassium hydroxide solution was kept overnight at room temperature andthen acidified with 2 N hydrochloric acid. The mixture was heated forhalf an hour on the steam bath, cooled, diluted with ice water and theproduct was extracted with several portions of ether. The combinedextract was washed with Water, dried over anhydrous sodium sulfate andthe ether was evaporated. There was thus obtained the65,19-oxidoandrostane-3p,l7 8-diol, M.P. l84-186 [ab-2.

Example III The above compound was dissolved in acetone, cooled to 0 C.and treated with a slow stream of 8 N chromic acid (prepared in the samemanner as described in Example I) under an atmosphere of nitrogen, withstirring and at 0 C. The precipitate was collected by filtration, washedwith water and dried under vacuum to thus af- 6 ford the6,8,19-oxido-androstane-3,17-dione, M.P. 165- 167"; [a] -|l25.

A mixture of 1.0 g. of the latter compound, 50 cc. of dioxane and 5.0 g.of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 24 hours.The mixture was cooled, filtered and the solvent was evaporated underreduced pressure. Recrystallization from acetone-hexane yielded the6/3-l9-oxido-A -audrostadiene-3,17-dione.

Example IV To 2 g. of 6B,19-oxido-androstane-3,17-dione (prepared in theprevious example) in cc. of glacial acetic acid there was added 2 molarequivalents of bromine dissolved in glacial acetic acid containing atrace of hydrogen bromide, with continuous stirring. After 4 hours atroom temperature water was added and the crude dibromide was collected.The crude product, 2,16-dibromo- 6B,19-oxido-androstane-3,17-dione in 20cc. of dimethylformamide was added to a boiling suspension of 1.5 g. ofcalcium carbonate in 30 cc. of dirnethylformamide and the mixture wasrefluxed for 30 minutes. The solution was cooled, filtered and thefiltrate was washed with dilute hydrochloric acid, sodium carbonatesolution and water. The dried extract was evaporated and the residue waschromatographed on 50 parts of neutral alumina to furnish613,19-oxido-l6-bromo-A -androstene-3,17-dione.

A solution of chromous chloride was prepared as follows: A mixture of 20g. of zinc dust, 1.6 g. of mercuric chloride, 20 cc. of water and 1 cc.of concentrated hydrochloric acid was stirred for 5 minutes in anatmosphere of carbon dioxide and the supernatant liquid was decanted;there was then added 40 cc. of water and 4 cc. of concentratedhydrochloric acid and finally 10 g. of chromic chloride in portions,under vigorous stirring and under an atmosphere of carbon dioxide. Therewas thus obtained a dark blue solution of chromous chloride.

The 65,19-oxido-l6-bromo n -androstene 3,17 dione was then dissolved in100 cc. of acetone and treated little by little under an atmosphere ofcarbon dioxide with 20cc. of the chromous chloride solution. The mixturewas kept at 0 Clandstirred from time to time and after 15 minutes, theproduct was precipitated by the addition of water, collected byfiltration, washed with water, dried under vacuum and recrystallizedfrom acetone, thus yielding 65,19-oxido-A androstene-3,17-dione.

Example V To 1.0 g. of 6B,19-oxido-A -androstene-3,17-dione in 50 cc. ofdioxane, there was added 3.0 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was refluxed for 20 hours.After the usual work-up, there was obtained 6B,19-oxido-A-androstadiene-3,l7-dione, identical with the product formed in ExampleIII.

Example VI A mixture of 1.0 g. of 65,19-oxido-androstane-3,l7- dione(cf. Example III), 8 cc. of ethylene glycol, 0.15 g. ofp-toluenesulfonic acid and 100 cc. of benzene was refluxed for six hourswith concomitant slow 'azeotropic distillation. The resulting solutionwas cooled, washed with an aqueous solution of potassium carbonate andevaporated to dryness. Recrystallization of the residue from heptaneafforded the 6B,19-oxido-17-ethylenedioxyandrostan-S-one.

To a solution of 2.0 g. of the above compound in 50 cc. of aqueoustetrahydrofuran, there was slowly added a solution of 0.5 g. of sodiumborohydride in 10 cc. of Water under stirring at room temperature andthe stirring was continued for three hours. The excess of hydride wasdecomposed by the addition of acetic acid, the solut-ion wasconcentrated to a small volume and then diluted with water. The productwas extracted with ethyl acetate and the extract was washed with water,dried and evaporated. Upon recrystallization from acetone-hexane, therewas obtained 6,8,19-oxido-17-ethylenedioxy-androstane-S/S-ol.

The l -l-:etal group was cleaved by treating the latter compound with 50mg. of p-toluenesulfonic acid in 12 cc. of acetone, allowing the mixtureto stand overnight at room temperature. Upon addition of water, therewas furnished 65,19-oxido-androstan-3B-ol-17-one.

Example VII A mixture of the above compound, 200 cc. of thiophene-freeanhydrous benzene and 45 cc. of a 3 N solution of methyl magnesiumbromide was refluxed for 6 hours; the mixture was then poured into 800cc. of water containing 30 g. of ammonium chloride and 800 g. of crushedice, with vigorous stirring. The benzene layer was separated, washedwith dilute hydrochloric acid and then with water to neutral, dried overanhydrous sodium sulfate and the benzene was evaporated. Crystallizationfrom acetone-hexane afiorded17m-methyl-6B,-19-oxidoandrostane-3fi,l7fi-diol.

A mixture of 2.0 g. of 17a-methyl-6fl,19-oxido-androstame-313,17/3-diol,10 cc. of pyridine and 10 cc. of acetic anhydride was allowed to remainovernight at room temperature. After the usual work-up, there wasobtained the 3-monoacetate of 17a-methy1-6/3,l9-oxido-androstane-35,175-dil.

In a similar conventional manner, there was also prepared thepropionate, butyrate, benzoate and cyclopentylpropionate.

Example VIII Upon treatment with acetic anhydride in benzene solutionand in the presence of p-toluenesulfonic acid, the 3-monoacetate of6,9,19-oxidol7a-methyl-androstane-3B, l7fl-diol was converted into thecorresponding 3,l7-diacetate.

Example [X By substituting propionic anhydride in the method of thepreceding example, there was prepared the S-acetate- 17-propionate of6B,19-oxido-l7a-methy1-androstane-3fi, 17,3-diol.

Other diesters such as the 3-propionate-17-acetate; 3-benzoate-17-acetate; and 3,17-dibutyrate were also prepared bysubstituting the appropriate acid anhydrides.

Example X To a solution of 2 g. of 65,19-oxido-androstan-3fl-oll7-one in250 cc. of absolute ether was added little by little a solution of 10molar equivalents of ethyl lithium in 50 cc. of ether with mechanicalstirring and under an atmosphere of nitrogen.

The mixture was then stirred for 48 hours at room temperature and underan atmosphere of nitrogen; after pouring into water, the mixture wasacidified with hydro chloric acid stirring vigorously for 1 hour. Theether layer was separated, washed with water to neutral, dried overanhydrous sodium sulfate, filtered and the ether was evaporated from thefiltrate. Recrystallization of the residue from acetone-hexane yielded17or-ethyl-6,B,19-oxidoandrostane-3fi,17B-diol.

Conventional esterification with acetic anhydride yielded thecorresponding 3-mono-acetate which upon further reaction with aceticanhydride in benzene solution and in the presence of p-toluenesulfonicacid was converted into the 3,17-diacetate.

Example XI A solution of 1 g. of potassium metal in 50 cc. of thutanolwas prepared under an atmosphere of nitrogen, cooled to 0 C, and treatedwith a cold solution of l g. of 6B,19-oxido-androstan-3fl-ol-17-one (cf.Example VI), little by little, under an atmosphere of nitrogen, at 0 C.and under continuous stirring. The nitrogen was then substituted by drypurified acetylene and a stream of this gas introduced into the mixturefor 40 hours. The solution was then poured into 200 cc. of dilutehydrochloric acid, stirred for 1 hour at room temperature and theorganic solvents were removed by steam distillation. The residue wascooled, the solid collected and recrystallized from acetone-hexane, thusfurnishing l7a-ethiny1-6p,19- oxido-androstane-3fl,17 8-di0l.

A solution of 500 mg. of the above compound in 10 cc. of pyridinecontaining 100 mg. of a pre-rcduced palladium on calcium carbonatecatalyst was hydrogenated at room temperature until the equivalents of 1mol of hydrogen had been absorbed; the catalyst was removed byfiltration; the pyridine was evaporated under reduced pressure and theresidue was triturated with 20 cc. of 1% hydrochloric acid; the productwas extracted with ethyl acetate and the extract was washed with water,dried over anhydrous sodium sulfate and evaporated to dryness. Bychromatography on neutral alumina there was obtained 17a-vinyl-63,l9-oxido-androstane-3f3,17fi-diol.

By applying the methods of esterification described in Examples VII,VIII and IX there were obtained the 3- monoacetates; 3,17-diacetates;3-acetate, 17-propionate; 3propionate,17-acetate; 3-benzoate-17-acetateand 3,17- dibutyrates of 17a-vinyl-6,B,l9oxido-androstane-3fl,17,9- dioland of l7a-ethinyl-6fl,19-oxido-androstane-3fi,17/3- diol.

Example XII To a solution of 2.5 g. of the diacetate of 17a-methyl-6/3,19-oxido-androstane-3B,17fl-diol (prepared in Example VIII) in 50cc. of acetic acid was added 2.5 g. of

chromium trioxide dissolved in 100 cc. of acetic acid, and the mixturewas kept at 90 for 1 hour. Finally the product was precipitated by theaddition of ice Water, collected and recrystallized from acetone-hexane,thus affording the 6,19-lactone of3,8,17fl-diacetoxy-17amethyl-androstan-6fi-ol-l9'carboxylic acid.

A solution of 2 g. of the above compound in cc. of 2% methanolicpotassium hydroxide solution was kept at room temperature overnight andthen acidified with 2 N hydrochloric acid. The mixture was heated forhalf an hour on the steam bath, cooled, diluted with ice water and theproduct was extracted with several portions of ether. The combinedextract was washed with water, dried over anhydrous sodium sulfate andthe ether was evaporated. There was thus obtained the 6,19-lactone of17a-methyl-androstane 313,65,17fi-triol-19-carboxylic acid.

Example XIII By substituting in the preceding example the 3,17-diacetateof l7u-methyl-6fi,l9-oxido-androstane-3fl,17fi-diol by the3,17-diacetate of 17a-ethyl-6/3,19-oxido-androstane- 3fi,17fl-diol,there was obtained the 6,19-lactone of 17aethyl3,8,17,8-diacetoxy-androstan-6B-ol-19 carboxylic acid and finally6,19-lactone of 17a-ethyl-androstane- 35,618,17,8-triol-19-carboxylicacid.

In a similar manner, the 3,17-diacetate of 17a-ethinyl-6B,19-oxido-androstane-3B,17,3-diol was converted into the corresponding6,19-lactone and finally into the free alcohol.

By substituting the diacetate by other diesters such as by the3-acetate-l7-propionate; 3-propionate-l7-acetate; 3-benzoate-17-acetateand the 3,17-dibutyrate in the above described method, there were formedthe 6,19-lactones of the corresponding esters of17a-methyl-androstane-3fi, 6,8,17/3-triol-l9-carboxylic acid, of17a-ethyl-androstane- 313,618,17B-triol-19-carboxylic acid; and of17a-ethinylandrostane-3B,613,17,8-triol-19-carboxylic acid.

Example XIV By partial hydrogenation of the 6,19-lactone of 17aethinyl-38,17/3-diacetoxy-androstan 6fl-ol-l9-carboxylic acid, described in thepreceding example, there was formed the 6,19-lactone of3p,17,6-diacetoxy-17u-vinylandrostan-fl-ol-l9-carboxylic acid.

Thus 1.0 g. of the 6,19-lactone of35,17fl-diacetoxyl7a-ethinyl-androstan-6,3-01-19-carboxylic acid in 20cc. of pyridine containing 200 mg. of a catalyst consisting of 2%palladium on barium sulfate was hydrogenated at room temperature. After35 minutes, the uptake of hydrogen was 1.05 mols and had virtuallyceased. The catalyst was removed by filtration through celite, the pyridine was evaporated under reduced pressure and the crude reactionproduct was purified by crystallization from acetone-hexane to give thepure product, the 6,19-lactone of 313,17B-diacetoxy-l7a-vinyl-androstan-6fl-ol-19- carboxylic acid.

By following the method described in Example XII, the above compound wasconverted into the free alcohol, namely, the 6,19-lactone ofl7oc-vinyl-androstane-3fl,618, 17fl-triol-l9-carboxylic acid.

Example XV By substituting in the method of the previous example, the6,19-lactone of3fi,l7fl-diacetoxy-17a-ethinyl-androstan-6fl-ol-l9-carboxylic acid bythe other diesters described in Example XIII, namely the3-acetate-17-propionate; 3-propionate-17-acetate; 3-benzoate-17-acetate;and the 3,17-dibutyrate of the 6,19-lactone of l7oc-ethinylandrostane-3B,6fl,17fi-triol-19-carboxylic acid, there were formed thecorresponding diesters of the 6,19-lactone of17u-vinyl-androstan-3fi,6fi,17,8-triol-19-carboxylic acid.

Example XVI A mixture of 2.0 g. of the 6,19-lactone offlea-methylandrostane-3;8,6B,l7/3-triol-l9-carboxylic acid, and 100 cc.of 90% acetic acid was treated with a solution of 450 mg. of chromiumtrioxide in 25 cc. of 90% acetic acid for V2 hour and maintaining thetemperature below 20 C. It was then kept at 25 C. for 3 hours, pouredinto water and the product was extracted with methylene chloride. Theextract was washed with aqueous sodium bicarbonate solution and withwater to neutral, dried over anhydrous sodium sulfate and evaporated.Recrystallization of the residue from acetone-hexane yielded the6,19-1actone of 17a-methyl-androsttine-6 3,17,9-dio1-3-one-19 carboxylicacid.

Example XVII By substituting in the preceding example the 6,19-1actoneof l7a-methyl-androstane-3fi,6p,l7p-triol-l9-carboxylic acid by the6,19-lactone of l7oc-ethyl-androstane- 35,613,17e-triol-19-carboxy1icacid, the 6,19-lactone of 17u-ethinyl-androstane-3[3,6B,17,8-triol-19carboxylic acid or by the 6,19-lactone of17oc-vinyl-androstane-318,65,17 3- triol-19-carboxylic acid andfollowing the procedure described in such example, there were preparedthe 6,19- lactone of 17ot-ethyl-androstane-63,l7fi-diol-3-one-19-carboxylic acid, the 6,19-1actone of17a-ethinyl-androstane- 618,175-dio1-3-one-l9-carboxylic acid and the6,19-lactone of 17a-vinyl-androstane-6e,17fi-diol-3-one-19-carboxylicacid.

Example XVIII A solution of 2 g. ofl7a-methyl-6fl,19-oxido-androstune-35,17B-diol in 20 cc. of acetone wastreated with an excess of an 8 N solution of chromic acid in accordancewith the method described in Example 1. After the usual work up therewas obtained 17a-methy1-6fi,19- oxido-androstan-l7fl-ol-3-one.

A mixture of 1 g. of the above compound, 50 cc. of acetic acid, 25 cc.of acetic anhydride and 1 g. of ptoluenesulfonic acid was allowed tostand at room temperature for 1 hour, it was then poured into waterstirred until the excess of anhydride was hydrolized, and thecrystalline product collected by filtration. The total product Wasdissolved in 20 cc. of methanol and treated at room temperature for 12hours with 250 mg. of potassium hydroxide; the solution was poured intowater, the precipitate filtered, dried and recrystallized fromacetoneether thus giving the acetate of 17a-methyl- 6p,19-oxido-androstan--ol-3-one.

Example XIX In accordance with the method of the preceding ex ample,l'iot-ethyl-dc,19-oxido-androstane-318,l7B-diol and 17u-ethinyl6fi,l9-oxido-androstane-3/8,17fl-diol were converted, respectively intol7a-ethy1-6B,19-oxido-androstanl7p-ol-3-one andl7a-ethinyl-6p,l9-oxido-androstan-17pol-3-one.

We claim:

1. A compound of the following formula:

I lfi i wherein R is selected from the group consisting of keto,fi-hydroxy and a fi-hydrocarbon carboxylic acyl group containing up to12 carbon atoms.

2. 6,8,19-oxido-androstane-3,l7-di0ne.

3. 6p,19-oxidoandrostan-3 8-o1-17-one.

4. 6,6,19-oxido-A -androstene-3,l7-dione.

5. 6p,19-oxido-A androstadiene-3,17-dione.

6. A compound of the following formula:

B ps

wherein R is selected from the group consisting of keto,

12. 65,19 oxido 17a ethinyl androstane 3p,17p-

diol-3,17-diacetate.

13. 6,8,19-oxido-17a-viny1-androstane-3p,17p-diol.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: